1 Dermatologists rely on visual (clinical widefield) and dermoscopic examination of skin lesions to guide the need 2 for biopsy. With this approach, sensitivity is high, but specificity tends to be quite variable and lower, resulting 3 in millions of biopsies of benign lesions every year. To improve specificity, several optical technologies are 4 being developed to noninvasively detect skin cancer. Of these, reflectance confocal microscopy (RCM) is the 5 furthest advanced in clinical utility, proven for diagnosing skin cancers with high sensitivity and specificity. 6 RCM imaging, guided by dermoscopy, detects skin cancers with 2 times superior specificity, and reduces the 7 benign-to-malignant biopsy rate by 2 times, compared to that with dermoscopy alone. In 2016, the Centers for 8 Medicare and Medicaid Services granted current procedural terminology (CPT) reimbursement codes for RCM 9 imaging of skin. RCM imaging combined with dermoscopy is now advancing into clinical practice, sparing pa- 10 tients from unnecessary biopsies of benign lesions. However, toward widespread acceptance and adoption, a 11 key challenge is that clinical widefield examination, dermoscopy and RCM imaging are currently performed as 12 three separate procedures with separate devices. Clinicians do not precisely know the location of RCM imag- 13 es relative to the surrounding contextual lesion morphology that is seen with clinical widefield examination and 14 dermoscopy, resulting in lower and more variable diagnostic accuracy (particularly, sensitivity, positive and 15 negative predictive values). We propose a novel solution: (i) a new objective lens with an integrated micro- 16 camera, to deliver a concurrent widefield image of the skin surface surrounding the location of RCM imaging; 17 (ii) a new software algorithm for widefield image-based tracking of the location of RCM images within a dermoscopic 18 field of view; (iii) a new diagnostic approach that will proactively use widefield imaging to locate RCM images in 19 dermoscopic images. We intend to deliver this integrated widefield clinical, dermoscopic and RCM imaging ap- 20 proach into the clinic, toward a new standard for more accurate, consistent and faster RCM imaging to guide 21 patient care. Preliminary studies with a ?mock? objective lens and micro-camera on a bench-top set-up 22 demonstrated excellent optical sectioning (~2 m) and resolution (~1 m) for RCM imaging, and accurate and 23 repeatable location of RCM fields-of-view within the widefield image. RCM images showed excellent cellular 24 and morphologic detail in vivo. Our specific aims are (1) to develop a handheld reflectance confocal micro- 25 scope with integrated widefield camera; (2) to develop image processing algorithms for real-time widefield im- 26 aging-guided tracking of RCM image locations within dermoscopic fields; (3) to test and validate performance 27 on 100 patients. Although our proposition is for skin lesions, the research will surely have wider impact for 28 imaging in other settings, particularly, with miniaturized confocal microscopes and endoscopes, which have 29 very small fields-of-view. We are a highly synergistic team from Montana State University, Memorial Sloan 30 Kettering Cancer Center, Northeastern University and Caliber Imaging and Diagnostics (formerly, Lucid Inc.).